Methods for in vivo evaluation of physiological conditions and/or organ or system function including methods to evaluate cardiopulmonary disorders such as chronic heart failure using polarized 129 Xe

• US 20030064023A1
• Filed: 09/06/2002
• Published: 04/03/2003
• Est. Priority Date: 09/20/2001
• Status: Active Grant

• Current Assignee: Polarean, Inc. (Polarean Imaging Plc)
• Original Assignee: Medi-Physics Incorporated (General Electric Company)
• Inventors: Marelli, Claudio, Driehuys, Bastiaan, Hall, Margaret
• Granted Patent: US 6,991,777 B2
• Time in Patent Office: Days
• US Class Current: 424/9.3
• CPC Class Codes: A61B 5/055 involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
• CPC Class Codes: G01R 33/485 based on chemical shift information [CSI] or spectroscopic imaging, e.g. to acquire the spatial distributions of metabolites
• CPC Class Codes: G01R 33/5601 involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
• CPC Class Codes: G01R 33/56308 Characterization of motion or flow; Dynamic imaging

Abstract

In certain embodiments, methods of the present invention obtain NMR spectroscopy signal data that corresponds to the behavior of the polarized ¹²⁹Xe at a selected site(s) in selected environments in vivo. The gas exchange signal data can be used to evaluate: (a) the thickness of a barrier, such as a membrane, lining, wall or width of a lumen; (b) the operational condition or function of a membrane, body system or portion thereof; (c) cerebral perfusion; and/or (c) the efficacy of a therapeutic treatment used to treat a diagnosed disorder, disease, or condition. Thus, the present invention provides methods for screening and/or diagnosing a disorder or disease, and/or methods for monitoring the efficacy of therapeutics administered to subject to treat a disorder or disease.

Claims

1. A minimally or non-invasive in vivo method for evaluating the thickness or width of a physiological barrier such as a membrane, lining, lumen, channel, or wall in a subject using dissolved-phase polarized ¹²⁹Xe, comprising:

delivering polarized ¹²⁹Xe gas in vivo to a subject having a first environment, a physiological barrier having a thickness, and a second environment opposing the first environment such that the polarized ¹²⁹Xe travels serially through the first environment, the barrier, and into the second environment, wherein the polarized ¹²⁹Xe has an associated different NMR signal chemical shift frequency in the first and second environments and the barrier;

destroying the polarization of the ¹²⁹Xe in the barrier and the second environment;

obtaining an NMR spectroscopic signal of the polarized gas in the subject at the second chemical shift to generate at least one dynamic data set of the NMR spectroscopic signal values over time representative of the behavior of the polarized ¹²⁹Xe as it crosses the barrier and enters the second environment;

evaluating the polarized gas transit time of the polarized gas, the gas transit time corresponding to the time it takes the polarized gas to travel across the barrier and then enter the second environment, based on data provided by said obtaining step; and

determining the thickness or width of the barrier based on data provided by said evaluating step.

3. A method according to claim 1, wherein the step of determining is used to measure barriers having a thickness or width in the range of about 1 micron to about 100 microns.

4. A method according to claim 1, wherein the first environment is the lung air space or pulmonary vasculature tissue, wherein the barrier comprises the alveolar-capillary membrane, and wherein the second environment is pulmonary blood.

5. A method according to claim 1, wherein the physiological barrier is one of the glomerular capillary membrane, bowel membrane, placental membrane, and blood brain barrier.

6. A method according to claim 1, wherein the obtaining step is carried out a plurality of times, including at least once while the subject is at rest and at least once when the subject is under actual or simulated physical activity.

7. A method according to claim 1, wherein the obtaining and evaluating steps are carried out to monitor the efficacy of a therapeutic agent administered to the subject.

8. A method according to claim 1, further comprising assessing the function of the alveolar-capillary membrane.

9. A method according to claim 1, further comprising generating an MR image of the anatomy of interest using a dual tuned ¹²⁹Xe and ¹H RF excitation coil.

10. A method according to claim 1, further comprising obtaining a polarized noble gas ¹²⁹Xe ventilation distribution MRI.

12. A method according to claim 1, further comprising:

generating a signal strength versus time curve to fit the dynamic data;

identifying a time constant of the curve; and

evaluating the amplitude of the signal strength at a time along the curve corresponding to the time constant.

13. A method according to claim 1, further comprising obtaining a second NMR spectroscopic signal of the polarized gas in the subject at the first chemical shift in the first environment to generate at least one dynamic data set of the NMR spectroscopic signal values over time;

and generating a signal strength versus time curve to fit the dynamic data for the first environment.

15. A method according to claim 1, further comprising evaluating at least one of glomerular filtration rate, acute and chronic renal failure, nephrotic syndrome, glomerulonephritis and other renal diseases.

16. A method according to claim 1, further comprising evaluating large and small bowel wall thickness, integrity or function.

17. A method according to claim 1, further comprising quantitatively evaluating placental membrane function.

18. A method according to claim 1, further comprising evaluating the blood brain barrier.

19. A method according to claim 1, further comprising evaluating the patient for respiratory ailments.

20. A method according to claim 9, wherein said delivering step is carried out via breath-hold inhalation.

21. A method according to claim 1, wherein the physiological barrier is a membrane or lining in the body of the subject.

22. A method according to claim 1, wherein the physiological barrier is the bowel wall.

23. A method according to claim 1, wherein the physiological barrier is the blood brain barrier.

24. A method according to claim 1, further comprising evaluating organ or brain perfusion based at least in part on said obtaining and evaluating steps.

25. A method according to claim 1, further comprising obtaining an NMR spectroscopic signal of the polarized gas in the subject at the first chemical shift to generate a second dynamic data set of the NMR spectroscopic signal values over time at the first chemical shift frequency, and wherein the first dynamic data defines a slope of the signal of polarized ¹²⁹Xe in tissue over time in millisecond resolution, generating curves fit to each of the dynamic data sets.

26. A method according to claim 25, wherein the second dynamic data set corresponds to polarized ¹²⁹Xe behavior in tissue, and wherein the peak amplitude of the associated curve represents tissue volume.

27. A method according to claim 1, further comprising generating a line of signal strength over time fit to the dynamic data, wherein the line has an associated time constant, an associated linear portion with a slope, and signal strength amplitude over time, and wherein said evaluating step considers parameters associated with the line, including at least one of, the time constant, the signal amplitude at a time corresponding to the time constant, the peak signal amplitude, and the slope associated with the linear portion of the curve.

2. A method according to claim 2, wherein the physiological barrier is the alveolar-capillary membrane, and wherein said obtaining and evaluating steps are carried out when the subject is at rest and then repeated while the subject is under stress by actual or simulated exercise to elevate the heart rate, and wherein said method further comprises comparing the gas transit times at rest and stress to thereby assess the function of the alveolar-capillary membrane.

11. A method according to claim 2, further comprising determining the presence or absence of chronic heart failure based at least in part on said calculating step.

14. A method according to claim 2, further comprising evaluating pulmonary fibrosis or pulmonary edema.

28. An in vivo method for evaluating the blood brain barrier in a subject, comprising:

delivering polarized ¹²⁹Xe in vivo to a subject such that it diffuses into the blood stream and across the blood brain membrane to be taken up in tissue in the brain across the membrane, the polarized gas in the blood and brain tissue having distinct corresponding polarized gas NMR chemical shift signal frequencies;

destroying the polarization of the polarized ¹²⁹Xe in the brain tissue;

obtaining an NMR spectroscopic signal of the polarized gas in the subject over time at the brain tissue chemical shift frequency to generate at least one dynamic data set of the NMR spectroscopic signal strength values over time;

evaluating the dynamic data; and

assessing the blood brain barrier based on data provided by said obtaining and evaluating steps.

29. A method according to claim 28, wherein the evaluating step evaluates the polarized gas transit behavior of the polarized gas, the gas transit time corresponds to the time it takes the polarized gas to travel across the membrane and then enter the brain tissue after said destroying step

30. A method according to claim 29, wherein the brain tissue is gray matter, and wherein the step of assessing includes determining the thickness of the blood brain barrier.

31. A method according to claim 28, wherein the obtaining step is carried out to monitor the efficacy of a pharmaceutical agent administered to the subject to evaluate its impact on the thickness of the blood brain barrier.

32. A method according to claim 31, wherein the obtaining step is carried out both before and after the administration of the agent to the subject.

33. A method according to claim 28, wherein the step of evaluating comprises assessing perfusion and ventilated oxygen levels in gray and white matter brain tissue based on data provided by said obtaining step.

34. A method of obtaining cerebral perfusion information, comprising:

administering polarized ¹²⁹Xe to a subject in vivo;

concurrently obtaining a plurality dynamic data sets of NMR spectrographic signal strength of the polarized ¹²⁹Xe in the brain of the subject representative of perfusion in the brain, each dynamic data set corresponding to a different chemical shift frequency;

repeating the obtaining step for a plurality of different compartments across the brain; and

generating at least one perfusion image of the brain based on the obtaining step, wherein the image comprises a plurality of voxels associated therewith, and wherein each voxel corresponds to a measure of perfusion in a predetermined number of compartmentalized regions in the brain.

35. A method according to claim 34, wherein the dynamic data sets correspond to the dynamic behavior of polarized ¹²⁹Xe in gray matter, polarized ¹²⁹Xe in white matter, and polarized ¹²⁹Xe in cerebral blood.

36. An in vivo method for evaluating at least one of the thickness of adequacy of function of a membrane or lining, comprising:

delivering polarized ¹²⁹Xe in vivo to a subject such that the polarized ¹²⁹Xe moves across the membrane or wall, the polarized gas in the membrane or wall having a corresponding polarized gas NMR chemical shift signal frequency;

obtaining an NMR spectroscopic signal of the polarized gas in the subject over time at the chemical shift frequency to generate at least one dynamic data set of the NMR spectroscopic signal strength values over time; and

evaluating at least one of (a) the adequacy of function of the membrane or lining and (b) determining the thickness of the membrane or lining based on the data provided by said obtaining step.

37. A method according to claim 36, further comprising generating a line of signal strength over time best fit to the dynamic data, the line having an associated time constant, and wherein the step of obtaining is carried out for a time which is greater than about two times the length of the time constant.

38. A method according to claim 37, wherein the evaluating step measures a membrane or lining with a thickness in the range of about 1 micron to about 100 microns.

39. A method according to claim 37, wherein the membrane is the glomerular capillary membrane.

40. A method according to claim 37, wherein the membrane is the bowel membrane.

41. A method according to claim 37, wherein the membrane is the placental membrane.

42. A method according to claim 37, wherein the membrane is the blood brain barrier.

43. A method according to claim 39, wherein the function evaluated comprises measuring glomerular filtration rate.

44. A method according to claim 39, wherein the method is used to monitor disease progression and therapy in subjects having one of glomerulonephritides, acute and chronic renal failure, nephrotic syndrome, and glomerulonephritis.

45. A method according to claim 40, wherein the method is carried out to evaluate at least one of large and small bowel wall function.

46. A method according to claim 37, wherein the evaluating step comprises assessing bowel membrane integrity and function for gastroenterological diseases.

47. A method according to claim 36, wherein the obtaining step is carried out to monitor the efficacy of a therapeutic administered to the subject.

48. A computer program product for evaluating bioactivity, physiology, and/or perfusion in vivo in a subject, the computer program product comprising:

a computer readable storage medium having computer readable program code embodied in said medium, said computer-readable program code comprising;

computer readable program code that obtains an NMR spectroscopic signal of polarized ¹²⁹Xe in the subject over time at at least one selected chemical shift frequency to generate at least one dynamic data set of the NMR spectroscopic signal strength values over time; and

computer readable program code that analyzes the dynamic data set for at least one of;

(a) quantifying the thickness of a physiologic barrier such as tissue, membrane, or lining (b) quantifying the width of a lumen or channel;

(c) evaluating the adequacy of physiologic function of certain biosystems or membranes;

(d) identify disruptions or compromised integrity of physiological barriers, structures, lumens, or channels and/or to identify disorders associated therewith; and

(e) to provide a cerebral perfusion map of the brain based on a concurrent acquisition of dynamic data at multiple chemical shifts associated with the brain across a plurality of compartments of the brain.